Fatty acid synthase (FAS) is a 270 kDa cytosolic protein that functions as a homodimer (7). FAS catalyzes the synthesis of palmitate from the condensation of malonyl-CoA and acetyl-CoA, and also plays an important role in energy homeostasis by converting excess carbon intake into fatty acids for storage. When necessary, these fatty acids provide energy via β- oxidation (8). Most fatty acids are supplied by diet, so endogenous synthesis usually is minimal. Consequently, FAS is expressed at low to undetectable levels in most normal human tissues.
In contrast, FAS is over expressed in a large number of human cancers, including cancer of the prostate, despite high levels of ambient fatty acids (8). Almost all fatty acids in tumor cells are produced via de novo synthesis, despite adequate nutritional supply (14-17). The principal enzymatic product of FAS is palmitic acid. Palmitoylation, as well as other lipid modifications such as myristoylation, represent key regulatory switches in most signal transduction pathways including the phosphatidylinositol 3′-kinase (PI3K) and the Wnt/β-catenin pathways.
FAS and Prostate Cancer
The prevalence of prostate cancer is extremely high and increases with age; one in 6 men in the US will be diagnosed with prostate cancer during his lifetime. Prostate cancer is a leading cause of male cancer-related death, second only to lung and colon cancer, and represents about 10% of all cancer deaths in men in the United States (1). Multiple factors contribute to the high incidence and prevalence of prostate cancer. Risk factors include age, family history and race but also high fat diet and obesity (2-6). In fact, higher body mass index (BMI) and adult weight gain increase the risk of dying from prostate cancer (6). Dietary intervention or regulation of metabolic pathways can therefore potentially affect prostate cancer incidence and perhaps tumor aggressiveness.
It has been shown that the FAS enzyme is over expressed throughout the natural history of a substantial proportion of prostate cancers beginning with prostatic intraepithelial neoplasia, and that its increased expression is associated with a distinctive gene expression signature (9). Experimental studies have shown that FAS inhibitors or RNA interference-mediated silencing of FAS induce apoptosis in various tumor cell lines and/or tumor xenografts in vivo (10, 11).
It has been shown that one-fourth of human prostate cancers have genomic amplification of FAS (12). This suggests that FAS over expression confers a selective growth advantage to tumor cells. The biochemical and metabolic basis for and consequences of this over expression are not well understood. Prostate adenocarcinomas over expressing FAS display aggressive biologic behavior (13). Among the theories put forth for the role of FAS in carcinogenesis is the altered composition of membrane phospholipids (13), possibly altering detergent-resistant membrane microdomains (lipid rafts) and, as a result, signal transduction. Formal proof of this mechanism has not been obtained even though it has been shown that the majority (85%) of de novo synthesized fatty acids end up in cell membranes (18). The principal enzymatic product of FAS is palmitic acid. Indeed, many of the effects that result from FAS inhibition by cerulenin can be partially rescued by palmitic acid (10, 19). Therefore, it has been hypothesized that lipid-based post-translational modification of proteins for signal transduction pathways, such as ras or wnt palmitoylation, may confer a selective proliferative or survival advantage to cancer cells (20).